Summary

Clinical characteristics.

Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).

Diagnosis/testing.

The diagnosis of genetic aHUS is established in a proband with aHUS and identification of a pathogenic variant(s) in one or more of the genes known to be associated with genetic aHUS. The genes associated with genetic aHUS include C3, CD46 (MCP), CFB, CFH, CFHR1, CFHR3, CFHR4, CFI, DGKE, and THBD.

Management.

Treatment of manifestations: Eculizumab (a human anti-C5 monoclonal antibody) to treat aHUS and to induce remission of aHUS refractory to plasma therapy; plasma manipulation (plasma infusion or exchange) to reduce mortality; however, plasma resistance or plasma dependence is possible. Eculizumab therapy may not be beneficial to those with aHUS caused by pathogenic variants in DGKE. Treatment with ACE inhibitors or angiotensin receptor antagonists helps to control blood pressure and reduce renal disease progression. Bilateral nephrectomy when extensive renal microvascular thrombosis, refractory hypertension, and signs of hypertensive encephalopathy are not responsive to conventional therapies, including plasma manipulation. Renal transplantation may be an option, although recurrence of disease in the graft limits its usefulness.

Prevention of primary manifestations: Plasma exchange and eculizumab prophylaxis may prevent disease recurrences in those with mutation of circulating factors (CFH, C3, CFB, and CFI).

Surveillance: Serum concentration of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin: (1) every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for those with normal renal function or chronic renal insufficiency as they are at risk for relapse; and (2) in relatives with the pathogenic variant following exposure to potential triggering events.

Agents/circumstances to avoid: Those with known aHUS should avoid if possible pregnancy and the following drugs that are known precipitants of aHUS: chemotherapeutic agents (including mitomycin C, cisplatin, daunorubimicin, cytosine arabinoside); immunotherapeutic agents (including cyclosporin and tacrolimus); and antiplatelet agents (including ticlopidine and clopidogrel). Plasma therapy is contraindicated in those with aHUS induced by Streptococcus pneumoniae because antibodies in the plasma of adults may exacerbate the disease.

Pregnancy management: Women with a history of aHUS are at increased risk for an aHUS flare during pregnancy and even a greater risk in the post-partum period; the risk for pregnancy-associated aHUS (P-aHUS) is highest during the second pregnancy. Women with complement dysregulation should be informed of the 20% risk for P-aHUS, and any pregnancy in these women should be closely monitored.

Evaluation of relatives at risk: While it is appropriate to offer molecular genetic testing to at-risk relatives of persons in whom pathogenic variants have been identified, predictive testing based on a predisposing factor (as opposed to a pathogenic variant) is problematic as it is only one of several risk factors required for aHUS.

Other: Live-related renal transplantation for individuals with aHUS should also be avoided in that disease onset can be precipitated in the healthy donor relative. Evidence suggests that kidney graft outcome is favorable in those with CD46 and DGKE pathogenic variants but not in those with C3, CFB, CFH, CFI, or THBD pathogenic variants; however, simultaneous kidney and liver transplantation in young children with aHUS and CFH pathogenic variants may correct the genetic defect and prevent disease recurrence.

Genetic counseling.

Autosomal recessive inheritance: Heterozygotes are usually asymptomatic; however, in rare cases, heterozygotes develop aHUS in adulthood. At conception, each sib of an individual with autosomal recessive aHUS has a 25% chance of inheriting two pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither pathogenic variant.

Autosomal dominant inheritance: Some individuals diagnosed with autosomal dominant aHUS have an affected parent or an affected close relative, but in the majority the family history is negative because of reduced penetrance of the pathogenic variant in an asymptomatic parent, early death of a parent, late onset in a parent (or close relative), or a de novo pathogenic variant in the proband. Each child of an individual with autosomal dominant aHUS has a 50% chance of inheriting the pathogenic variant.

In both genetic types, clinical severity and disease phenotype often differ among individuals with the same pathogenic variants; thus, age of onset and/or disease progression and outcome cannot be predicted. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant(s) have been identified in the family.

Diagnosis

Suggestive Findings

Genetic atypical hemolytic-uremic syndrome (aHUS) should be suspected in a proband with a diagnosis of aHUS in addition to ONE of the following criteria:

Two or more members of the same family have been diagnosed with aHUS at least six months apart and exposure to a common triggering infectious agent has been excluded.

An individual has an HUS relapse even after complete recovery from the presenting episode.

An underlying environmental factor such as drugs, systemic disease, viral agents, or bacterial agents that do not result in Shiga-like exotoxins can be identified.

For information about laboratory findings and renal histology related to typical and atypical HUS, click here.

Establishing the Diagnosis

The diagnosis of genetic aHUS is confirmed in a proband with aHUS and identification of a pathogenic variant(s) in one or more of the genes known to be associated with genetic aHUS (see Table 1). Genetic predisposition to aHUS can be inherited in an autosomal dominant or autosomal recessive manner by a pathogenic variant(s) in a single gene; or, rarely, inheritance can be polygenic. To date, the reported mechanisms include the following:

A multigene panel that includes C3, CD46, CFB, CFH, CFI, DGKE, and THBD should be considered in individuals with aHUS presenting after age one year. Testing specifically designed to detect CFH/CFHR1 and CFHR1/CFH hybrid alleles and deletions of CHFR1/CHFR4 and CHFR3/CHFR1 should also be considered. Note: The high degree of sequence identity between CFH and its downstream CFH-related genes (CFHR1-CFHR4) results in susceptibility to non-allelic homologous recombination (NAHR) events, and consequently, in large-scale deletions or duplications (copy number variation) and generation of hybrid CFH genes. Molecular assays must be specifically designed to detect deletions resulting from gene conversion in this region.

Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single exon deletions or duplications.

Malignancy-associated aHUS occurs in almost 6% of individuals with metastatic carcinoma. Gastric cancer accounts for approximately half of such cases.

Post-transplantation aHUS may occur in individuals who have not had aHUS before or may affect those whose primary cause of ESRD was aHUS.

Pregnancy-associated aHUS may occasionally develop as a complication of preeclampsia. Some women progress to a life-threatening variant of preeclampsia with severe thrombocytopenia, microangiopathic hemolytic anemia, renal failure, and liver involvement (HELLP syndrome). Complete remission usually follows prompt delivery. Post-partum aHUS usually manifests in women within three months of delivery. The outcome is usually poor: ESRD or death in 50%-60%; residual renal dysfunction and hypertension are the rule in those who survive the acute episode.

Phenotype Correlations by Gene

The phenotype of aHUS ranges from mild (with complete recovery of renal function) to severe (resulting in ESRD or death). The course and outcome of the disease are influenced by the gene in which pathogenic variants occur.

C3. Atypical HUS associated with C3 pathogenic variants presents in childhood in about 50% of individuals. More than 60% of affected individuals will develop ESRD.

CD46. Atypical HUS associated with CD46 pathogenic variants typically presents in childhood with a milder acute episode. Eighty percent of individuals experience complete remission. Recurrences are frequent but have little effect on long-term outcome; 60%-70% of individuals remain dialysis free even after several recurrences. A subgroup of individuals, however, lose renal function either during the first episode or later in life.

CFH. Atypical HUS associated with CFH pathogenic variants presents early in childhood in approximately 70% of affected individuals and in adulthood in approximately 30%. Irrespective of the pattern of inheritance, there is a high rate of relapse and a 60%-80% rate of ESRD or death.

DGKE. Atypical HUS associated with biallelic pathogenic variants in DGKE presents before age one year in all affected individuals [Lemaire et al 2013]. Affected individuals show persistent hypertension, hematuria, and proteinuria (sometimes in nephrotic range). Relapsing episodes are reported before age five years. Chronic kidney disease occurs by the second decade of life.

THBD. Atypical HUS associated with THBD pathogenic variants presents in childhood in about 90% of individuals. More than 50% of individuals will eventually develop ESRD.

Polygenic inheritance.CFH, CFI, and C3 pathogenic variants may have an additive effect and lead to a more severe aHUS phenotype in individuals with CD46-associated aHUS, including an increased incidence of ESRD and graft loss [Bresin et al 2013].

Differential Diagnosis

Typical HUS triggered by Stx-E. coli manifests as an acute disease with a prodrome of diarrhea (D+HUS), often bloody. However, approximately 25% of typical HUS is diarrhea negative. During an acute episode, identification of Shiga toxins in the stools (by the Vero cell assay) and/or serum antibodies against Shiga toxin (by enzyme-linked immunosorbent assay [ELISA]) and/or LPS (O157, O26, O103, O111, and O145, by ELISA) distinguishes typical HUS (D+HUS or D–Stx+HUS) from aHUS (D–Stx–HUS). The detection of free fecal STEC (Shiga toxin-producing E. coli) can be made by commercial immunoassays and requires only a few hours [Gianviti et al 2003]. Approximately 80%-90% of individuals recover without sequelae, either spontaneously (as in most cases of childhood typical HUS) or after plasma infusion or exchange (as in adult or severe forms of typical HUS) [Ruggenenti et al 2001]. Typical HUS usually subsides when the underlying condition is treated or removed.

Note: STEC isolation and detection of LPS antibodies are not routinely available and require a few days to complete.

Distinguishing aHUS from thrombotic thrombocytopenic purpura (TTP). Atypical HUS and TTP (OMIM 274150) share a common pathologic lesion (thrombotic microangiopathy) but have different clinical manifestations. In aHUS the lesions and clinical symptoms are mainly localized in the kidney, whereas the pathologic changes of TTP are more extensively distributed. Clinically, TTP manifests mainly with central nervous system symptoms, but renal insufficiency has been reported.

Approximately 80% of TTP is triggered by deficient activity of ADAMTS13. ADAMTS13 deficiency can be constitutive, as a result of biallelicADAMTS13 pathogenic variants; or acquired, as a result of an inhibitory antibody. Evaluation of ADAMTS13 activity is performed using tests based on the capability of the protease to cleave standard VWF multimers in vitro (e.g., collagen binding assay). Deficiency of ADAMTS13 activity is not found in individuals with HUS [Galbusera et al 2006]. The exception occurs when ADAMTS13 and CFH pathogenic variants are observed in the same individual. Affected individuals with both ADAMTS13 and CFH pathogenic variants have been reported [Noris et al 2005, Zimmerhackl et al 2007].

Distinguishing aHUS from C3 glomerulopathy (C3G), a glomerulonephritis characterized by renal accumulation of complement C3. C3G is identified by glomerular changes in which there is C3 dominant staining at immunofluorescence, with absence or near absence of immunoglobulins. The two major subgroups of C3G include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Clinically, C3G presents with proteinuria, hematuria, and often some degree of renal failure. In DDD, acquired partial lipodystrophy and ocular drusen may also be seen. Median age at C3G diagnosis is 21 years; DDD presents earlier with a mean age at diagnosis of 14 years. Ten-year progression to ESRD is higher in DDD (36%-50%) than in C3GN (25%). Recurrence of disease and allograft loss after transplantation is common (50%-75%) [Xiao et al 2014].

C3G is associated with alternative pathway complement activation usually caused by C3 nephritic factors, IgG autoantibodies that stabilize the alternative C3 convertase (C3bBb), or by pathogenic variants in complement genes. C3Nefs are found in 60%-70% of individuals with C3G [Xiao et al 2014]. Also anti-CFH autoantibodies have been identified in a few individuals with C3G. Multiple genetic causes have been reported in individuals with C3G. These include biallelicCFH pathogenic variants that cause severely reduced CFH protein levels found in autosomal recessive cases of DDD or C3GN [Zipfel et al 2015], heterozygousC3 pathogenic variants in familial cases of DDD [Martínez-Barricarte et al 2010] and also in individuals with C3GN [Valoti et al 2013], and copy number variations in the CFHRgene cluster (duplication in CFHR5 or in CFHR1, CFHR2deletion, extra copy of CFHR2-CFHR5, extra copy of CFHR3-CFHR1) found in individuals with C3G [Zipfel et al 2015].

However, the rare individuals with aHUS associated with homozygous pathogenic variants in CFH and very low levels of circulating CFH protein can blur the distinction between HUS and C3G. Furthermore, this overlap in phenotypes is evident in those few individuals who have a mixed diagnosis of aHUS and C3G in the same biopsy or in biopsies taken at different points in time [Gnappi et al 2012].

Treatment of Manifestations

Eculizumab has been shown to induce remission of acute episodes of aHUS refractory to plasma therapy and is now widely used as a first-line therapy to treat aHUS. Eculizumab should be considered as a first-line therapy when the diagnosis of aHUS is unequivocal, since this treatment has the potential to rescue renal function when administered early after onset of the disease [Zuber et al 2012a, Fakhouri et al 2013].

Plasma infusion or exchange guidelines have been published for children [Ariceta et al 2009] and adults [Taylor et al 2010]. Cohort data show that response to plasma therapy was in part related to the genetic background of the treated patient [Noris et al 2010]. Despite the variability in response to therapy, plasma therapy is the only therapy with near-complete global availability and therefore it remains an important treatment for aHUS. Plasma therapy should be started as soon as aHUS is suspected and continued until resolution of thrombotic microangiopathy. In individuals who respond, plasma exchange can be gradually withdrawn, although a significant proportion will require continued plasma exchange to maintain remission. There is minimal evidence to suggest the superiority of either plasma exchange or plasma infusion, and instead the selected option should be based on individual tolerance, local expertise, and resources (e.g., a neonatal benefit from infusion vs exchange) [Nester et al 2015].

Plasma exchange usually involves exchanging 1-2 plasma volumes (40 mL/kg) per session in adults and 50-100 mL/kg in children. Typically, plasma exchange is undertaken daily initially; the duration and frequency of treatment is then determined by the clinical response.

Treatment can be intensified by increasing the volume of plasma replaced. Twice-daily exchange of one plasma volume is probably the treatment of choice for those with refractory disease in order to minimize the recycling of infused plasma.

Plasma infusion is the first-line therapy when plasma exchange or eculizumab therapies are not available. In plasma infusion 30-40 mL/kg of plasma is administered initially, followed by 10-20 mL/kg/day. Plasma infusion should be used to treat or prevent recurrent episodes.

Platelet count and serum LDH concentration are the most sensitive markers for monitoring response to plasma therapy. Plasma treatment should be continued until platelet count and serum LDH concentration remain normal after therapy is discontinued. Discontinuation of plasma therapy is the only way to know if complete remission has been achieved. Immediate exacerbation of disease activity, principally manifested by falling platelet count that requires the resumption of daily plasma therapy, occurs in 29%-82% of individuals after treatment is discontinued. Thus, many cycles of stopping and resuming plasma therapy may occur, in which case therapy with eculizumab should be considered.

Genetic characterization of persons with aHUS has the potential to optimize the treatment:

C3. Response to plasma treatment in persons with C3 pathogenic variants was comparable (57%) to that in persons with CFH pathogenic variants [Noris et al 2010]. It is hypothesized that plasma exchange could remove mutated hyperactive C3 and also provide regulatory plasma proteins to counteract complement activation induced by mutated C3.

CD46. The rationale for using plasma in individuals with CD46 pathogenic variants is not so clear, since the CD46 protein (also known as MCP) is a transmembrane protein and, theoretically, plasma infusion or plasma exchange would not compensate for the MCP defect. Published data indicate that the majority (80%-90%) of individuals undergo remission following plasma infusion or exchange [Richards et al 2003, Caprioli et al 2006]; however, complete recovery from the acute episode was also observed in 100% of individuals not treated with plasma [Noris et al 2010]. The decision whether or not to treat with plasma should be based on the clinical severity of the acute episode.

CFH. Plasma infusion or exchange has been used in individuals with aHUS and CFH pathogenic variants with the rationale of providing normal CFH to compensate for the genetic deficiency, as CFH is a circulating plasma protein. In published studies, some individuals with CFH pathogenic variants did not respond at all to plasma therapy and died or developed ESRD. Others required infusion of plasma at weekly intervals in order to raise CFH plasma levels enough to maintain remission [Landau et al 2001].

Stratton and Warwicker [2002] were able to induce sustained remission in a patient with a CFHpathogenic variant by three months of weekly plasma exchange in conjunction with intravenous immunoglobulins. One year after discontinuation of plasma therapy, the patient remained disease free and dialysis independent.

A dozen case reports showed that early plasma therapy, generally consisting of daily plasma exchange followed by maintenance plasma exchange/infusion, could prevent relapses and preserve renal function at follow up for up to six years [Loirat et al 2016].

In the authors' series [Caprioli et al 2006, Noris et al 2010], approximately 60% of individuals with CFH pathogenic variants treated with plasma underwent either complete or partial remission (hematologic normalization with renal sequelae). However, the remaining individuals did not respond at all to plasma and 20% died during the acute episode.

In the French cohort [Frémeaux-Bacchi et al 2013] progression to ESRD during the first episode of aHUS was similar in children and adults with CFH pathogenic variants who received high-intensity plasma therapy compared to those who did not.

CFH autoantibodies. In individuals with anti-CFH autoantibodies, plasma treatment induced complete or partial remission (normalization of hematologic parameters with renal sequelae) of 75% of episodes [Noris et al 2010]. Persons with anti-CFH autoantibodies benefit from treatment with steroids or other immunosuppressants in conjunction with plasma exchange.

CFI. Theoretically one should expect a good response to plasma therapy in individuals with CFI pathogenic variants because CFI (like CFH) is a circulating protein; the results, however, suggest that a larger quantity of plasma is required to provide sufficient wild-type CFH or CFI to compensate for the genetic deficiency [Caprioli et al 2006]. Indeed, remission was achieved in only 25% of episodes treated with plasma in persons with CFI pathogenic variants [Noris et al 2010].

DGKE. Absence of evidence linking DGKE deficiency to the complement cascade and relapses of acute aHUS in affected individuals with pathogenic variants in DGKE while receiving plasma therapy suggest that this treatment may not benefit individuals with DGKE pathogenic variants [Lemaire et al 2013].

Treatment with ACE inhibitors or angiotensin receptor antagonists helps to reduce renal disease progression to end-stage renal failure, while at the same time controlling blood pressure levels.

Bilateral nephrectomy may serve as rescue therapy in selected individuals with extensive microvascular thrombosis at renal biopsy, refractory hypertension, and signs of hypertensive encephalopathy, in whom conventional therapies including plasma manipulation are not adequate to control the disease (i.e., persistent severe thrombocytopenia and hemolytic anemia). Follow up has been excellent in some individuals [Ruggenenti et al 2001].

Renal transplantation outcome is determined largely by the underlying genetic abnormality. An important advance has been the development of transplant protocols integrating eculizumab treatment [Nester et al 2011]. Eculizumab therapy may be used to treat post-transplantation aHUS recurrence, as reported in individuals with pathogenic variants in C3, CFH, and CFI [Zuber et al 2012b]. Eculizumab prophylactic therapy may also prevent post-transplantation aHUS recurrence (see Prevention of Secondary Complications).

Molecular genetic testing can help to define graft prognosis; thus, all affected individuals should undergo such testing prior to transplantation.

C3, CFB, and CFI. Graft failures secondary to recurrences occurred in one individual with a CFBpathogenic variant and in70% of individuals with CFI pathogenic variants. The percentage of graft failure was slightly lower (50%) in individuals with C3 pathogenic variants [Noris et al 2010].

CD46. Four individuals with isolated
CD46 pathogenic variants have undergone renal transplantation with no disease recurrence [Noris & Remuzzi 2005, Noris et al 2010]. The strong theoretic rationale is that because the CD46 protein (MCP) is a transmembrane protein that is highly expressed in the kidney, transplantation of a kidney expressing normal MCP corrects the defect.

CFH. In individuals with CFH pathogenic variants the graft outcome is poor. Recurrence ranges from 30% to 100% and is significantly higher than in individuals without CFH pathogenic variants [Noris & Remuzzi 2010]. As CFH is mainly produced by the liver, kidney transplantation does not correct the CFH genetic defect in these individuals.

Simultaneous kidney and liver transplantation has been performed in two young children with aHUS and CFH pathogenic variants [Noris & Remuzzi 2005]. However, following transplantation both children experienced premature irreversible liver failure. The first child recovered after a second uneventful liver transplantation. This child, who had had monthly recurrences of aHUS before transplantation, had no symptoms of aHUS for more than two years following transplantation. The second child expired after primary non-function of the liver graft followed by multiorgan failure.

In six other individuals with CFH pathogenic variants and in one child heterozygous for pathogenic variants in two genes (CFH and CFI) who received simultaneous kidney and liver transplantation [Saland et al 2006, Saland et al 2009, Noris et al 2010], good renal and liver function were recorded at two-year follow up. In these individuals, extensive plasma exchange was given prior to surgery to provide enough normal CFH to prevent damage to the liver graft.

DGKE. Three individuals with aHUS caused by pathogenic variants in DGKE received cadaveric renal transplantation at ages 2, 19, and 21 years [Lemaire et al 2013]. Two allografts have survived two years and four years, till last observation, whereas the other failed after six years due to chronic rejection. Importantly, there were no aHUS recurrences after transplantation. On the basis of these findings, it appears that renal transplantation can be efficacious and safe in individuals with aHUS caused by pathogenic variants in DGKE.

THBD. One individual with THBD pathogenic variants had disease recurrence in the kidney graft – an unexpected occurrence, as thrombomodulin (like CD46) is an endothelial transmembrane protein. However, a soluble thrombomodulin form circulates in plasma and has functional activities similar to those of membrane-bound thrombomodulin. It is possible that the grafts were not sufficiently protected against complement activation because of dysfunctional soluble thrombomodulin in persons with THBD pathogenic variants [Noris et al 2010].

Prevention of Primary Manifestations

Plasma exchange prophylaxis has been shown to prevent disease recurrences in persons with mutation of CFH [Davin et al 2008]. Plasma exchange and eculizumab prophylaxis may prevent disease recurrences in those with mutation of circulating factors (CFH, C3, CFB, and CFI).

Prevention of Secondary Complications

Eculizumab has a greater efficacy than plasma therapy in the prevention of thrombotic microangiopathic events, with earlier intervention associated with a greater clinical benefit [Legendre et al 2013]. Eculizumab can be used as a prophylactic treatment to prevent post-transplantation aHUS recurrence in those at moderate to high risk of recurrence, as defined below [Nester et al 2011, Weitz et al 2011, Krid et al 2012, Zuber et al 2012b]:

Individuals with pathogenic variants in C3, CFB, and CFH or those who have the CFH-CFHR1 hybrid allele are at high risk for disease recurrence [Zuber et al 2012b].

In those who are not vaccinated two weeks prior to therapy with eculizumab, daily prophylactic antibiotics (e.g., oral penicillin or a macrolide) should be administered for two weeks following vaccination.

Since currently available vaccines do not cover all N meningitidis strains, a few countries require continuous antibiotic prophylaxis throughout eculizumab treatment.

In children treated with eculizumab, vaccination against Streptococcus pneumonia and Haemophilus influenza type B infections is also required.

Surveillance

Individuals with known aHUS. Measure serum concentration of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, and C4, and haptoglobin:

Every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for persons with normal renal function or chronic renal insufficiency as they are at risk for relapse. Note: Individuals with ESRD usually do not relapse.

Every two weeks for those rare individuals with homozygousCFH pathogenic variants that result in very low or undetectable levels of the CFH protein

Note: The proposed time intervals for checking hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin are suggestions [Authors, personal observation]; each center may follow different guidelines based on their own experience.

Agents/Circumstances to Avoid

Discontinue cyclosporine or tacrolimus when aHUS develops following challenge with the medication.

Fresh frozen plasma should be avoided (i.e., plasma therapy is contraindicated) in persons with aHUS induced by Streptococcus pneumoniae because plasma from an adult contains antibodies against the Thomsen-Friedenreich antigen, which may exacerbate the disease. It is preferable to transfuse washed red blood cells or platelets. There is no evidence that plasmapheresis is of value [Copelovitch & Kaplan 2008].

Avoid potential precipitants of aHUS, including the following known triggers of aHUS:

Evaluation of Relatives at Risk

Molecular genetic testing should be offered to at-risk family members of persons in whom a pathogenic variant(s) has been identified.

Note: Testing of family members needs to be done with caution because presence of the family-specific pathogenic variant(s) is predisposing rather than causative, and thus is only one of several risk factors required for development of aHUS. Predictions based on a single risk factor in unaffected individuals are unreliable (see Penetrance). Therefore, risk cannot be quantified for a given individual.

The following are appropriate for relatives in whom the family-specific pathogenic variant(s) have been identified:

Monitoring of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin) when exposed to potential triggering events such as severe infections, inflammation, and pregnancy (see Surveillance)

Pregnancy Management

Women with a history of aHUS are at increased risk for aHUS flare during pregnancy and an even greater risk in the post-partum period. Pregnancy-associated aHUS (P-aHUS) occurred in 21 of 100 adult women with aHUS, with 79% presenting post partum [Fakhouri et al 2010]. Treatment consisted mainly of plasma exchange, and the outcomes were poor with 62% developing end-stage renal disease by one month after presentation and 76% by last follow up. The risk for P-aHUS was highest during a second pregnancy. Complement abnormalities were found in 18 of the 21 adult women with P-aHUS. Pregnancies in affected women with complement abnormalities were complicated by fetal loss (in 4.8%) and preeclampsia (7.7%).

On the basis of these results, women with complement dysregulation should be informed of the 20% risk for P-aHUS, and any pregnancy in these women should be closely monitored.

Therapies Under Investigation

Research efforts are aimed at identifying more specific approaches that may interfere with the primary cause of microangiopathy in the different forms of aHUS.

For aHUS associated with CFH pathogenic variants:

Specific replacement therapies with recombinant CFH protein could become a viable alternative to plasma treatment.

Efforts are also ongoing to isolate plasma fractions enriched in CFH protein that could provide sufficient active CFH while minimizing the risk of allergy and fluid overload associated with standard plasma infusion therapy. A CFH protein concentrate under development for clinical use has recently achieved Orphan Drug designation by European Medicines Agency (EMEA) and the FDA.

The discovery of pathogenic variants in three different complement-regulatory genes provides sufficient evidence to undertake clinical trials using complement inhibitors that block the activation of C3 [Kirschfink 2001]. Studies on other complement-regulatory genes would help to clarify the molecular determinants underlying the pathogenesis of aHUS and potentially improve management and therapy.

Advances in vector safety and transfection efficiency may eventually make gene therapy a realistic option.

Other

Plasma-resistant/plasma-dependent disease. Some individuals with aHUS are plasma resistant (i.e., they do not achieve remission despite plasma therapy); some become plasma dependent, experiencing disease relapse as soon as plasma infusion or exchange is stopped.

Splenectomy – while it induces remission in some persons with plasma resistance – is ineffective and actually increased morbidity and mortality in others.

Other treatments including antiplatelet agents, prostacyclin, heparin or fibrinolytic agents, steroids, and intravenous immunoglobulins have been attempted in both plasma resistance and plasma dependence with no consistent benefit [Ruggenenti et al 2001].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with
information on the nature, inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members. This section is not meant to address all personal, cultural, or
ethical issues that individuals may face or to substitute for consultation with a genetics
professional. —ED.

If both parents of a proband with a known pathogenic variant are unaffected, molecular genetic testing for the pathogenic variant identified in the proband should be offered to both parents. If a pathogenic variant is identified in a parent, the parent is at risk of developing aHUS and of transmitting the pathogenic variant to other offspring.

If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include:

The family history of individuals with autosomal dominant aHUS may appear to be negative because of reduced penetrance of the pathogenic variant in an asymptomatic parent, early death of a parent, or late onset in a parent (or close relative). Therefore, an apparently negative family history cannot be confirmed unless the parents have been tested for the pathogenic variant identified in the proband.

Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression and outcome cannot be predicted.

The risk to the sibs of the proband depends on the genetic status of the parents:

If a parent of the proband has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, sibs who inherit the pathogenic variant may or may not develop aHUS.

If the pathogenic variant found in the proband cannot be detected in DNA extracted from the leukocytes of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.

Clinical severity and disease phenotype often differ among individuals with the same pathogenic variants; thus, age of onset and/or disease progression and outcome cannot be predicted.

Clinical severity and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression and outcome cannot be predicted.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is heterozygous for an aHUS-related pathogenic variant, his or her family members may be at risk.

At conception, each sib of an individual with autosomal recessive aHUS has a 25% chance of inheriting two pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither pathogenic variant.

Sibs who inherit biallelicDGKE pathogenic variants typically have clinical features of aHUS before age one year.

Age of onset and/or disease progression and outcome cannot be predicted in sibs who inherit biallelic pathogenic variants in other aHUS-related genes as clinical severity and disease phenotype often differ among individuals with the same pathogenic variants because of the role of environmental triggers.

Heterozygotes (carriers) are usually asymptomatic. Rare cases of heterozygotes developing aHUS in adulthood have been reported [Caprioli et al 2006].

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Risk to Family Members – Polygenic Inheritance

Polygenic aHUS is caused by the simultaneous presence of two pathogenic variants: one pathogenic variant in one complement-regulatory gene and another pathogenic variant in a different complement-regulatory gene.

Typically, one parent has a pathogenic variant in one complement-regulatory gene and the other parent has a pathogenic variant in a different complement-regulatory gene. However, both parents should undergo confirmatory genetic testing because it is possible that one parent has both pathogenic variants and is asymptomatic.

Heterozygotes are usually asymptomatic.

Sibs of a proband. Assuming that each parent has one pathogenic variant, at conception each sib has a 75% chance of inheriting one or two pathogenic variants (and being at increased risk of developing aHUS) and a 25% chance of not inheriting a pathogenic variant (and being unaffected).

Offspring of a proband. The risk to offspring of inheriting one or two pathogenic variants is 75%.

Related Genetic Counseling Issues

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant(s) in the family.

Precipitation of aHUS in renal donors. In two families, renal transplantation precipitated disease onset in the previously healthy donor [Donne et al 2002]. Subsequent molecular genetic testing revealed that one of the donors had a CFHpathogenic variant that put him at risk for aHUS. Thus, molecular genetic testing is recommended before live related donation to avoid the risk of triggering disease in the donor.

Family planning

The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.

Data are compiled from the following standard references: gene from
HGNC;
chromosomelocus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.

Normal gene product.C3 encodes complement component C3. Mainly produced by the liver, C3 is the pivotal component of the complement system. The mature protein is made by 1641 amino acids that form a beta chain and an alpha chain. C3 is processed by proteolytic cleavage by enzymatic complexes, the C3 convertases, into the anaphylatoxin C3a and the C3b fragment that deposits on cell surfaces causing the activation of the complement cascade. The alpha and beta chains form 13 domains including eight homologous domains called macroglobulin (MG) domains, the linker domain (LNK), the anaphylatoxin (ANA) domain, the CUB domain, the thioester-containing (TED) domain, and finally the C345c domain.

Gene structure.CD46 is an estimated 43 kb long and comprises 14 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The majority of CD46 pathogenic variants are heterozygous and cluster in the exons encoding the four N-terminal extracellular short consensus repeats (SCRs). No deletions or duplications involving CD46 as causative of aHUS have been reported. To date, about 70 CD46 pathogenic variants have been reported in individuals with aHUS [FH aHUS Mutation Database] with a variant frequency of 5%-9% among all individuals with aHUS [Nester et al 2015].

The list of published and unpublished pathogenic variants within CD46 is continuously updated in the FH aHUS Mutation Database.

Normal gene product.CD46 encodes the membrane cofactor protein (MCP), a widely expressed transmembrane glycoprotein. MCP serves as a cofactor for CFI protein to cleave C3b and C4b deposited on the host cell surface [Goodship et al 2004]. MCP has four extracellular N-terminal SCRs important for their inhibitory activity, followed by a serine-threonine-proline rich domain, a transmembrane domain, and a cytoplasmic tail.

Table 2.

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Twelve heterozygous pathogenic variants in CFB [Marinozzi et al 2014] have been reported in individuals with aHUS, with a frequency of <1%-4% [Nester et al 2015]. The majority of CFB pathogenic variants cluster in the exons that encode the VWA (von Willebrand factor type A) domain. No deletions or duplications involving CFB as causative of aHUS have been reported.

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

The list of published and unpublished pathogenic variants within CFH is continuously updated in the FH aHUS Mutation Database.

More than 100 different CFH pathogenic variants have been reported in individuals with aHUS [Saunders et al 2006]. The vast majority of CFH pathogenic variants in individuals with aHUS are heterozygous and cause either single amino-acid changes or premature translation terminations that primarily cluster in the C-terminus domains and are commonly associated with normal CFH protein plasma levels. A minority of the pathogenic variants result in the production of a truncated protein or impaired secretion of protein [Pérez-Caballero et al 2001, Richards et al 2001, Caprioli et al 2006].

A heterozygous hybrid allele of CFH and CFHR1, derived by non-allelic homologous recombination (NAHR) from a crossing over between intron 21 of CFH and intron 4 of CFHR1 (CFH-related 1), was found in five persons with aHUS [Venables et al 2006]. The hybrid allele consists of the first 21 exons of CFH (encoding short consensus repeats [SCRs] 1-18 of CFH) and the last two exons of CFHR1 (encoding SCR4 and SCR5 of CFHR1). The frequency of this heterozygous hybrid allele in aHUS is estimated at 3%-5%.

A heterozygous hybrid allele of CFH and CFHR1, derived by NAHR from a crossing over between intron 22 of CFH and intron 5 of CFHR1 has been found in two persons with aHUS [Maga et al 2011]. The novel hybrid allele consists of the first 22 exons of CFH (encoding SCRs 1-19) and the last exon of CFHR1 (encoding SCR5 of CFHR1). The frequency of this novel heterozygous hybrid allele in aHUS is estimated at 1.5% [Maga et al 2011].

More recently, two novel similar hybrid CFHR1/CFH alleles have been found in three persons with aHUS. In one individual, the breakpoint was found located between intron 4 of CFHR1 and intron 20 of CFH, resulting in a fusion protein containing the first three SCRs of CFHR1 and the terminal two SCRs of CFH [Eyler et al 2013]. In two related subjects the breakpoint was located between intron 5 of CFHR1 and exon 23 of CFH, resulting in a fusion protein containing the first four SCRs of CFHR1 and the terminal SCR20 of CFH [Valoti et al 2015].

Normal gene product. Mainly synthesized by the liver, the complement factor H (CFH) protein is a 150-kd single-chain plasma glycoprotein and consists of 20 homologous structural domains called SCRs (short consensus repeats), each of which comprises approximately 60 amino acids. CFH plays an important role in the regulation of the alternative pathway of complement. It serves as a cofactor for the C3b-cleaving enzyme, factor I (encoded by CFI) in the degradation of newly formed C3b molecules and controls decay, formation, and stability of the C3b convertase C3bBb. The complement-regulatory domains needed to prevent fluid phase alternative pathway amplification have been localized within the N-terminal SCR1-4 [Rodríguez de Córdoba et al 2004].

The inactivation of surface-bound C3b is dependent on the binding of the C-terminal domain of CFH protein to polyanionic molecules that increases CFH protein affinity for C3b and exposes its complement-regulatory N-terminal domain. The C-terminal domain contains two C3b-binding sites, located in SCR12-14 and SCR19-20, and three polyanion-binding sites, located in SCR7, SCR13, and SCR19-20 [Józsi et al 2004]. However, the C3b- and the polyanion-binding sites located in SCR19-20 are required for CFH to inactivate surface-bound C3b, since deletion of this portion of the molecule renders CFH protein incapable of blocking complement activation on sheep erythrocytes.

Abnormal gene product. Expression and functional studies demonstrated that CFH proteins with aHUS-associated pathogenic variants (deriving from single-nucleotide variants, gene conversion, and a hybrid allele) have a severely reduced ability to interact with polyanions and with surface-bound C3b [Józsi et al 2004], resulting in a lower density of mutated CFH molecules bound to endothelial cell surface and a diminished complement-regulatory activity on the cell membrane [Józsi et al 2004]. In contrast these mutants have a normal capacity to control activation of the complement in plasma, as indicated by their retention of normal cofactor activity in the proteolysis of fluid-phase C3b.

Interestingly, the protein product of the hybrid alleleCFH/CFHR1 is identical to another CFH mutated allele with two pathogenic variants in cis configuration, p.[Ser1191Leu;Val1197Ala], which arises by gene conversion between CFH and CFHR1 and whose protein product lacks surface complement-regulatory activity.

CFHR1, CFHR3, and CFHR4

Gene structure.CFHR3, CFHR1, and CFHR4 (previously known as CFHL3, CFHL1, and CFHL4, respectively) are contiguous genes that occur in this relative order on chromosome 1 at 1q31-q32.1. These genes are in the regulators of complement activation (RCA) cluster. Each comprises six exons; reference sequences are NM_021023.5, NM_002113.2, and NM_006684.4. For a detailed summary of gene and protein information, see Table A, Gene.

CFHR1 encodes a secreted protein which belongs to the complement factor H protein family. It binds to Pseudomonas aeruginosa elongation factor Tuf together with plasminogen, which is proteolytically activated.

Both CFHR3 and CFHR4 enhance the cofactor activity of factor H in C3b inactivation.

Abnormal gene product. Complete absence of both CFHR1 and CFHR3 proteins was detected in about 10% of aHUS [Zipfel et al 2007, Moore at al 2010]. CFHR1/CFHR3 plasma deficiency is associated in the large majority of cases with the formation of anti-CFH autoantibodies. These antibodies bind both to CFHR1 and to the CFH C-terminal [Moore et al 2010], reduce CFH binding to C3b, and enhance alternative pathway dependent lysis of sheep erythrocytes without influencing fluid-phase cofactor activity. The causal link between CFHR1-R3 deletion and CFH autoantibodies is as yet unknown.

More recently, three affected individuals positive for anti-CFH autoantibodies were found to have no copies of CFHR1 but a single copy of CFHR3 and a novel deletion incorporating CFHR1 and CFHR4. In these individuals a CFHR3/CFHR1 deletion was present on one allele and a CFHR1/CFHR4 deletion on the other allele, suggesting that the complete deficiency of factor H-related protein 1 was probably the significant factor associated with the production of factor H autoantibodies in aHUS [Moore et al 2010].

CFI

Gene structure.CFI is approximately 63 kb long and comprises 13 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

The list of published and unpublished pathogenic variants within CFI is continuously updated in the FH aHUS Mutation Database.

Normal gene product. Mainly produced by the liver, complement factor I (CFI) protein is an 88-kd plasma serine-protease with a modular structure. It is a heterodimer and consists of a non-catalytic 50-kd heavy chain linked to a catalytic 38-kd light chain by a disulphide bond. CFI cleaves and inactivates C3b and C4b.

Gene structure.THBD is approximately 4.03 kb long and comprises a single exon. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. About 5% of persons with aHUS have been found to have heterozygousTHBD pathogenic variants [Delvaeye et al 2009, Noris et al 2010]. All THBD pathogenic variants are heterozygous and cluster in the lectin-like domain and in the serine-threonine (ST)-rich peptide.

Normal gene product. Thrombomodulin is a 557-amino-acid endothelial glycoprotein that is anchored to the cell by a short cytoplasmic tail and a single transmembrane domain that is followed by a ST-rich domain. A series of six epidermal growth factor-like repeats are required for thrombin-mediated generation of activated protein C, which has anticoagulant and cytoprotective properties, and the generation of activated thrombin-activatable fibrinolysis inhibitor (TAFI), which has C3a-degrading and C5a-degrading properties. Farthest from the transmembrane domain is the lectin-like domain, which confers resistance to pro-inflammatory stimuli, including endotoxin. Thrombomodulin facilitates complement inactivation by CFI in the presence of CFH.